Properdin deficiency or anti-properdin treatment ameliorates disease in the C3 gain-of-function mouse model of atypical haemolytic uraemic syndrome.

Introduction: We have previously shown that the C3D1115N mouse, engineered around a single point mutation in C3 associated with atypical haemolytic uraemic syndrome (aHUS) in man, fully recapitulates the clinical disease. In this study, we investigated the role of properdin in aHUS. Methods: C3D1115N mice were crossed onto properdin-deficient mice or C3D1115N mice were treated with anti-properdin monoclonal antibody therapy and survival tracked. Kidney function, serum biomarkers and kidney pathology was carefully assessed at set end points. C3 and Fibrin deposition was assessed using immuno-fluorescence. Results: We have found that removing properdin ameliorates disease, although two mice had evidence of renal disease over a ~6-month period. Therapeutic treatment with an anti-properdin monoclonal antibody (14E1) after evidence of clinical disease was sufficient to block the progression of disease, suggesting that measures to reduce the stability of the alternative pathway C3 and C5 convertases can help prevent thrombotic microangiopathic anaemia (TMA)/aHUS. Discussion: Our data indicate that a fine balance exists between disease progression and resolution in our C3 gain-of-function model. The data also suggest that anti-properdin therapy, as noted in another mouse model of TMA, may provide a viable treatment option to maintain remission in complement mediated aHUS.